Shailendra Verma

Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy

UNLABELLEDnPURPOSE; Pertuzumab, a human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibody, potently inhibits HER2 dimerization and HER-mediated signaling pathways. Pertuzumab and the approved HER2-targeted monoclonal antibody trastuzumab have complementary mechanisms of action and result in enhanced antitumor activity when combined. This phase II trial assessed the efficacy and safety profile of the combination in patients with HER2-positive breast cancer whose disease had progressed during prior trastuzumab-based therapy.nnnPATIENTS AND METHODSnThis was a multicenter, open-label, single-arm, Simon two-stage study. Patients with advanced HER2-positive breast cancer in whom disease progression had occurred during prior trastuzumab-based therapy received trastuzumab weekly (4 mg/kg loading dose, then 2 mg/kg every week) or every 3 weeks (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) and pertuzumab every 3 weeks (840 mg loading dose, then 420 mg every 3 weeks). Treatment continued until disease progression or excessive toxicity.nnnRESULTSnAll 66 patients were assessable for efficacy and safety. The objective response rate was 24.2%, and the clinical benefit rate was 50%. Five patients (7.6%) experienced a complete response, 11 patients (16.7%) experienced a partial response, and 17 patients (25.8%) experienced stable disease of > or = 6 months. Median progression-free survival was 5.5 months. Overall, the combination of pertuzumab and trastuzumab was well tolerated, and adverse events were mild to moderate. Cardiac dysfunction was minimal, and no patients withdrew as a result of cardiac-related adverse events.nnnCONCLUSIONnThe combination of pertuzumab and trastuzumab is active and well tolerated in patients with metastatic HER2-positive breast cancer who had experienced progression during prior trastuzumab therapy.

The effects of green tea consumption on incidence of breast cancer and recurrence of breast cancer: a systematic review and meta-analysis.

Background: Green tea is widely used by women for the prevention and treatment of breast cancer. The authors aimed to determine the efficacy of green tea ingestion on the risk of breast cancer development and the risk of breast cancer recurrence. Methods: The authors conducted a systematic review and meta-analyses of observational studies from systematic searches of 8 electronic data sources and contact with authors. They included studies assessing breast cancer incidence and recurrence. Results from cohort studies and case-control studies were pooled separately using a random effects model with testing of a priori hypotheses to explain heterogeneity. Results: The pooled relative risk (RR) of developing breast cancer for the highest levels of green tea consumption in cohort studies was 0.89 (95% confidence interval [CI], 0.71-1.1; P = .28; I2= 0%), and in case control studies, the odds ratio was 0.44 (95% CI, 0.14-1.31; P = .14; I2= 47%). The pooled RR of cohort studies for breast cancer recurrence in all stages was 0.75 (95% CI, 0.47-1.19; P = .22; I2= 37%). A subgroup analysis of recurrence in stage I and II disease showed a pooled RR in cohort studies of 0.56 (95% CI, 0.38-0.83; P = .004; I2= 0%). Dose-response relationships were evident in only 3 of the 7 studies. Conclusion: To date, the epidemiological data indicates that consumption of 5 or more cups of green tea a day shows a non-statistically significant trend towards the prevention of breast cancer development. Evidence indicates that green tea consumption may possibly help prevent breast cancer recurrence in early stage (I and II) cancers. However, conclusions as to the potential therapeutic application of green tea are currently impossible to make due to the small number of studies conducted, the lack of any clinical trial evidence, the lack of a consistent dose-response relationship, and the potential for interaction with standard care.

Selection of adjuvant chemotherapy for treatment of node-positive breast cancer

Over the past two decades, several studies have suggested that regimens that contain anthracyclines are more effective than those that do not. A meta-analysis by the 2005 Early Breast Cancer Trialists Collaborative Group confirmed that about 6 months of anthracycline-based polychemotherapy in the adjuvant setting reduced the yearly death rate from breast cancer by about 38% for women younger than 50 years and by 20% for women aged 50-69 years. Although this meta-analysis found that survival was better with regimens that contain anthracycline than with regimens based on cyclophosphamide, methotrexate, and fluorouracil, the best use of anthracycline-based regimens remains unclear. Adjuvant regimens in use can be categorised into three groups: standard-dose anthracycline; escalated-dose epirubicin; and anthracyclines and taxanes. The duration of treatment and combination of dose and drugs varies between these three categories. We reviewed the three types of regimen to establish which provide a better outcome in terms of safety, efficacy, cost, and convenience to patients. We found that both escalated-dose epirubicin and anthracycline-taxane regimens were most effective in terms of disease-free survival and overall survival. Of the specific anthracycline-based regimens, the docetaxel, doxorubicin, and cyclophosphamide regimen (TAC); the fluorouracil, 100 mg epirubicin, and cyclophosphamide regimen (FEC100); and the cyclophosphamide, epirubicin, and fluorouracil regimen (CEF) produced the greatest proportional decreases in 5-year death rate.

Phase III double-blind comparison of dolasetron mesylate and ondansetron and an evaluation of the additive role of dexamethasone in the prevention of acute and delayed nausea and vomiting due to moderately emetogenic chemotherapy.

PURPOSEnTo compare the efficacy of dolasetron and ondansetron in controlling nausea and vomiting in the first 24 hours; to evaluate the efficacy when dexamethasone is added to either drug in the first 24 hours; and to extend these comparisons over 7 days in patients receiving moderately emetogenic chemotherapy.nnnPATIENTS AND METHODSnThis was a multicenter, double-blind, randomized study with six parallel arms that used a 2 x 2 factorial design in chemotherapy-naive patients. In arm 1, dolasetron (2.4 mg/kg) was given intravenously (I.V.) prechemotherapy, followed 24 hours later by oral dolasetron (200 mg once daily) for 6 days. Arms 2 and 3 consisted of dolasetron and dexamethasone 8 mg I.V., followed 24 hours later by oral dexamethasone (8 mg once daily) in one arm, and oral dexamethasone and dolasetron in the other, also for 6 days. In arms 4, 5, and 6, ondansetron (32 mg I.V. or 8 mg orally twice daily) was administered in a similar manner to arms 1, 2, and 3 before and 24 hours after chemotherapy. Mean nausea severity (MNS) was assessed on a visual analog scale (VAS) in a daily diary.nnnRESULTSnOf 703 patients enrolled, 696 were eligible. There were 343 dolasetron- and 353 ondansetron-treated patients; 57% of dolasetron-treated patients had complete protection in the first 24 hours versus 67% of patients who received ondansetron (P = .013). MNS was also more pronounced on the dolasetron arm (P = .051). Sixty-seven percent of patients who received added dexamethasone in the first 24 hours had complete protection, compared with 55% without dexamethasone (P < .001). MNS was significantly reduced with the addition of dexamethasone (P < .001). At 7 days, dolasetron and ondansetron had equivalent complete protection rates (36% and 39%, respectively). With the addition of dexamethasone, 48% of patients compared with 28% had complete protection (P < .001). MNS was significantly improved with added dexamethasone (P < .001).nnnCONCLUSIONnAt the doses used, dolasetron was significantly less effective than ondansetron at controlling nausea and vomiting in the first 24 hours in patients receiving moderately emetogenic chemotherapy, but there was no demonstrable difference between both drugs over 7 days. The addition of dexamethasone significantly improved the efficacy of both drugs in the first 24 hours and over 7 days.

The Role of Economic Evidence in Canadian Oncology Reimbursement Decision-Making: To Lambda and Beyond

OBJECTIVEnThe overarching question addressed in this article is: what has been the impact of economic evidence to Canadian drug reimbursement decisions; within this, has an (explicit or implicit) threshold been identified for making such decisions; and is the impact or threshold different for oncology medications?nnnMETHODSnThree sequential strategies were employed: a literature search, a review of publicly available Canadian reimbursement recommendations, and a one-day key informant roundtable, held with a purposive sample of 13 individuals from across Canada to gain information not readily accessible from the public domain.nnnRESULTSnDespite the formal requirement for structured economic evidence, the limited public information suggests that its uptake in the Canadian decision-making process has been tentative. Implicit economic thresholds have been published in Australia and the United Kingdom, but not in Canada. Based on reviews of reimbursement recommendations, thresholds specific to oncology medications may be higher than for nononcology medications, in Canada and elsewhere. Canadian reimbursement recommendations can appear inconsistent with respect to clinical evidence, economic evidence, and nonevidentiary factors, possibly because of a lack of transparency or context-sensitive interpretations. The key informant roundtable provided reasons for the inconsistent uptake of economic evidence: panelists were divided between those who found economic information useful and supportive to decision-making, and those who did not. Panelists generally agreed on the need for publicly defensible and ethical reimbursement restrictions. They suggested the following improvements: transparency of processes and decisions, dynamic formularies that can adapt with evolving treatment practices and clinical data, broader representation of expertise on review panels, greater use of ethics to resolve conflicts arising from different perspectives, and the development of an explicit Canadian weighting system for evidence and values.nnnCONCLUSIONSnEconomic evidence has been tentatively incorporated in reimbursement decision-making in Canada. Public reasons for recommendation indicate that this evidence is used primarily with respect to the attractiveness of an incremental cost-effectiveness ratio. Oncology drugs seem to be adopted at the highest thresholds of acceptability. Yet, decision-makers expressed a need to move beyond lambda, rejecting the simplicity of the incremental cost-effectiveness ratio and considering alternative strategies to improve decision-making, including formal guidance for weighting both evidence and values.

The role of the 5-HT3 antagonists ondansetron and dolasetron in the control of delayed onset nausea and vomiting in patients receiving moderately emetogenic chemotherapy

BACKGROUNDn5-HT3 antagonists are effective in reducing the acute nausea and vomiting caused by cancer chemotherapy. However, it is not clear whether continuing these agents beyond twenty four hours is useful in controlling emesis on days two to seven after chemotherapy.nnnPATIENTS AND METHODSnFour hundred seven patients receiving moderately emetogenic chemotherapy who had been given dexamethasone 8 mg i.v. and either ondansetron 32 mg i.v. or dolasetron 2.4 mg/kg i.v. were randomized to continue either an oral form of their 5-HT3 antagonist (ondansetron 8 mg b.i.d. or dolasetron 200 mg daily) plus dexamethasone 8 mg p.o. daily or dexamethasone alone for days two to seven. Endpoints assessed by self-report were: 1) complete control (no vomiting, no rescue medications, no missing data) of emesis; 2) nausea severity; and 3) quality-of-life as measured by the EORTC QLQ-C30.nnnRESULTSnContinuation of 5-HT3 antagonists improved slightly, but not significantly, the complete control rate (47% vs. 41%: P = 0.24 one-sided) after chemotherapy. However, mean nausea severity was significantly (P = 0.015 one sided) reduced (by 3 mm on a 10 cm scale) on the combined arm. Minimal differences in quality of life were observed.nnnCONCLUSIONnThe benefit of continuing 5-HT3 antagonists beyond 24 hours is modest and the merits of routine use in these circumstances debatable.

Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen

OBJECTIVEnThe goal of this work was to study the role of transvaginal ultrasonography (TVUS) together with colorflow Doppler imaging (CFDI) in the detection of significant endometrial abnormalities induced by tamoxifen.nnnMETHODSnOver a 6-year period, 304 women on tamoxifen as adjuvant therapy for breast cancer were recruited into the current study. Standard demographic data as well as duration of tamoxifen use were collected. Patients were assessed at study entry and at yearly intervals with TVUS together with CFDI. All patients had an endometrial biopsy at the time of study entry, and repeat endometrial evaluations were done subsequently only if there were abnormal ultrasound findings or the presence of irregular vaginal bleeding. All ultrasonic characteristics and Doppler flow measurements were recorded. Descriptive statistics were used to describe the study group. Logistic regression was used to identify significant treatment- and ultrasound-related factors associated with the presence of significant uterine pathology.nnnRESULTSnOne thousand and sixty-one ultrasound assessments were performed on 304 patients over a 6-year period. The mean age was 52.33 (range, 29-79). Seventy-two percent of the patients were postmenopausal at the time of breast cancer diagnosis. The median concentrations of estrogen and progesterone receptor were 75 and 73 fmol/L, respectively. Fifty-eight percent of the patients had received cytotoxic chemotherapy. The mean duration of tamoxifen use was 48.2 months. Thirty-two percent of the ultrasound examinations had associated significant uterine pathology defined as conditions that required further medical or surgical investigation and treatment. However, 80% of the abnormalities represented benign polyps. Six cases of primary endometrial cancer were detected. All cases presented with irregular bleeding. No recurrence of disease was detected at a median follow-up of 48 months. One case of metastatic breast cancer to the uterus was encountered. By setting the endometrial thickness cutoff at more than 9 mm to represent significant abnormality in this patient population, the sensitivity was 63.3%, specificity was 60.4%, positive predictive value was 43.3%, and negative predictive value was 77.5%. To detect endometrial cancer, the endometrial thickness cutoff at 9 mm had a positive predictive value of only 1.4%. Logistic regression analysis showed only endometrial thickness greater than 9 mm (OR 3.99, CI = 1.26-12.65, P = 0.018) and spiral artery pulsatility index measurement (OR 4.18, CI = 1.25-13.92, P = 0.02) to be associated with significant uterine abnormalities.nnnCONCLUSIONSnRoutine sequential ultrasound surveillance in asymptomatic women on tamoxifen is not useful because of its low specificity and positive predictive value. A significant portion of screened asymptomatic women would need to undergo needless surgical evaluations of their endometrium if widespread use of ultrasound is implemented in this patient population.

Cost utility analysis of first-line hormonal therapy in advanced breast cancer: comparison of two aromatase inhibitors to tamoxifen.

Recent randomized clinical trials (RCT) comparing anastrozole (Arimidex) and letrozole (Femara) to tamoxifen in the first-line treatment of postmenopausal women with advanced hormone-sensitive breast cancer have demonstrated that both agents were at least as effective as tamoxifen. In addition, one RCT has revealed significant superiority of letrozole to tamoxifen with regard to tumor response rate and time to progression. Based on the efficacy and toxicity data, anastrozole or letrozole may replace tamoxifen. A cost effectiveness analysis was undertaken to determine whether the new agents are economically acceptable alternatives to tamoxifen. In the absence of a randomized three-arm trial, a decision model was developed to simulate and compare the most common therapeutic outcomes. The clinical data were obtained from a meta analysis of modern (i.e., post-1990) randomized trials. Clinical outcomes data from the various trials were statistically pooled using a random effects model to provide point estimates and 95% confidence intervals. Total hospital resource consumption was collected from the charts of 87 patients with advanced disease who had failed tamoxifen therapy. The model suggested a comparable duration of quality-adjusted progression-free survival between letrozole and anastrozole, both being superior to tamoxifen (179 days vs. 172 days vs. 161 days). Letrozole and anastrozole had overall costs of Can

Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.

2,883 and

A Randomized Phase II Study of Cisplatin Alone Versus Cisplatin Plus Disulfiram

2,847 per patient, respectively, which were marginally higher than tamoxifen at